We are currently studying a variety of tumor-derived factors with effects on tumor-associated vasculature. These include vascular endothelial growth factor (VEGF) and endothelial cell monocyte-activating polypeptide II (EMAP-II). These cytokines appear to be produced in varying amounts by tumors and have direct effects on the tumor neovasculature. Our approach to the study of these interactions has been through the utilization of a variety of in vitro and in vivo model systems. We are using gene expression profiling to understand the changes that occur in endothelial cells exposed to tumor-derived factors. The laboratory is developing techniques, which allow us to isolate endothelial cells from tumor tissue. This has resulted in our ability to study tumor-derived endothelial cells directly, and has led to our observation that tumor associated endothelial cells have epigenetic changes compared to normal endothelial cells from the same tissue type. We are also using noninvasive imaging techniques, including dynamic MRI and PET, to map changes in tumor blood flow within tumors both in animal models and in our patients on clinical trials. A variety of inhibitors of tumor angiogenesis are being actively studied. These include both recombinant proteins derived from naturally occurring substances as well as small molecules designed to act on specific pathways. Various methods of delivering these agents, including gene therapy approaches and the use of tumor targeted nanoparticles are being pursued. Our overall goal is to translate a better understanding of tumor cell-endothelial cell interactions into better therapies for our patients with cancer.